Co-administration Of Morphine Research Articles

Repeated Administration of Baclofen Modulates TRPV-1 Channel Expression by PKC Pathway in Dorsal Root Ganglia of Spinal Cord in Morphine Tolerance Model of Rats

Background:Tolerance and dependence to anti-nociceptive effect of morphine restricted its use. Nowadays co-administration of morphine and other drugs suggests diminishing this tolerance. Baclofen is one of the drugs that may be beneficial in the attenuation of tolerance to morphine. Studies have shown that changes in TRPV-1 expression during administration of morphine have a pivotal role in developing morphine tolerance. Therefore, the effect of baclofen on TRPV-1 expression during chronic administration of morphine was investigated in this study. Methods:A total of 48 rats were divided into four groups of control, morphine single injection, morphine tolerance, and morphine tolerance + baclofen. To induce morphine tolerance in rats, animals received 10 mg/kg of i.p. morphine sulfate once a day for 10 days. In the treatment group, baclofen (0.5 mg/kg) was injected for 10 days, before morphine injection. Finally, to evaluate baclofen treatment on morphine analgesia and hyperalgesia, thermal hyperalgesia and formalin test were used. TRPV-1 and PKC expression and protein production in DRG of spinal cord were then evaluated by real-time PCR and Western blot. Results:In baclofen treatment group, thermal hyperalgesia and formalin test improved in comparison with morphine tolerance group. In morphine tolerance group, both TRPV-1/PKC gene expression and protein levels increased in comparison with the control group. However, following the baclofen treatment, the TRPV-1 and PKC levels decreased. Conclusion:Baclofen can enhance anti-nociceptive effect of morphine by modulating TRPV-1 channel and PKC activity.

Ghrelin receptor agonist hexarelin attenuates antinociceptive tolerance to morphine in rats.

Ghrelin, a peptide hormone released from the gastric endocrine glands, shows analgesic activity apart from its various physiological effects. Nevertheless, the effects of ghrelin receptor (GHS-R) agonists on morphine analgesia and tolerance have not yet been elucidated. The purpose of this study was to evaluate the effects of the ghrelin receptor agonist hexarelin and antagonist [d-Lys3]-GHRP-6 on morphine antinociception and tolerance in rats. A total of 104 Wistar albino male adult rats (weighing approximately 220-240g) were used in the experiments. To induce morphine tolerance, a three-day cumulative dose regimen was used in the rats. Then, randomly selected rats were evaluated for morphine tolerance on day4. The analgesic effects of hexarelin (0.2mg·kg-1), [d-Lys3]-GHRP-6 (10mg·kg-1), and morphine (5mg·kg-1) were measured at 30-min intervals (0, 30, 60, 90, and 120min) by tail-flick and hot-plate analgesia tests. The findings suggest that hexarelin in combination with morphine attenuates analgesic tolerance to morphine. On the other hand, ghrelin receptor antagonist [d-Lys3]-GHRP-6 has no significant analgesic activity on the morphine tolerance in analgesia tests. Furthermore, co-administration of hexarelin and morphine increases the analgesic effect. In conclusion, these data indicate that administration of GHS-R agonist hexarelin with morphine enhances the antinociception and attenuates morphine tolerance.

Co-Administration of Morphine and Naloxone: Histopathological and Biochemical Changes in the Rat Liver

Background: Co-administration of opioid agonists and antagonists at low doses has been reported to significantly enhance and/or prolong the analgesic effects and reduce or prevent tolerance to or dependence on opioids. Objectives: The current study aimed at evaluating the naloxone effect on morphine-induced histopathological and hematologic changes in rats. Materials and Mehods: Thirty mature male Wistar rats were categorized into three groups (n = 10) in a random manner, including the control group receiving normal saline, the morphine-sole group receiving morphine (5 mg/kg/day), and morphine + naloxone group receiving morphine and naloxone (5 and 0.4 mg/kg/day, respectively). After 50 days, the levels of alanine aminotransferase (ALT), alkaline phosphatase (ALP), triglyceride (TG), aspartate aminotransferase (AST), cholesterol, and high-density lipoprotein (HDL) were measured in the serum. Moreover, the levels of superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), and glutathione peroxidase (GPx) were measured to assess the serum antioxidant capacity. Histopathological changes were investigated via hematoxylin and eosin, Masson’s trichrome, and periodic acid-Schiff staining. Inter-group comparisons were made by GraphPad Prism software using one-way ANOVA and Tukey’s test. Results: The animals in the morphine + naloxone group showed higher AST, ALP, ALT, and CAT levels in comparison with the control and morphine-sole groups (P < 0.05). Our findings revealed no changes in the cholesterol, TG, SOD, and GPx levels among the groups (P > 0.05). However, the morphine-sole group exhibited higher serum levels of HDL compared with the controls (P < 0.05). The morphine-sole group showed fibrosis, local necrosis, immune cell infiltration, and diminished intra-cytoplasmic carbohydrate storage. Conclusions: The findings suggest that apart from unchanged serum markers, morphine can potentially induce hepatotoxicity, and at the same time, naloxone is able to ameliorate morphine-induced histopathological damages.

Suppression of active phase voluntary wheel running in male rats by unilateral chronic constriction injury: Enduring therapeutic effects of a brief treatment of morphine combined with TLR4 or P2X7 antagonists.

The present series of studies examine the impact of systemically administered therapeutics on peripheral nerve injury (males; unilateral sciatic chronic constriction injury [CCI])-induced suppression of voluntary wheel running, across weeks after dosing cessation. Following CCI, active phase running distance and speed are suppressed throughout the 7-week observation period. A brief course of morphine, however, increased active phase running distance and speed throughout this same period, an effect apparent only in sham rats. For CCI rats, systemic co-administration of morphine with antagonists of either P2X7 (A438079) or TLR4 ((+)-naloxone) (receptors critical to the activation of NLRP3 inflammasomes and consequent inflammatory cascades) returned running behavior of CCI rats to that of shams through 5+weeks after dosing ceased. This is a striking difference in effect compared to our prior CCI allodynia results using systemic morphine plus intrathecal delivery of these same antagonists, wherein a sustained albeit partial suppression of neuropathic pain was observed. This may point to actions of the systemic drugs at multiple sites along the neuraxis, modulating injury-induced, inflammasome-mediated effects at the injured sciatic nerve and/or dorsal root ganglia, spinal cord, and potentially higher levels. Given that our data to date point to morphine amplifying neuroinflammatory processes put into motion by nerve injury, it is intriguing to speculate that co-administration of TLR4 and/or P2X7 antagonists can intervene in these inflammatory processes in a beneficial way. That is, that systemic administration of such compounds may suppress inflammatory damage at multiple sites, rapidly and persistently returning neuropathic animals to sham levels of response.

Melatonin alleviates morphine analgesic tolerance in mice by decreasing NLRP3 inflammasome activation

Morphine is frequently used for pain relief, but long-term morphine therapy in patients with chronic pain results in analgesic tolerance and hyperalgesia. There are no effective therapeutic treatments that limit these detrimental side effects. We found pretreatment with melatonin could decrease morphine-induced analgesic tolerance. There was a significant activation of the NLRP3 inflammasome in the prefrontal cortex and the peripheral blood of morphine-treated mice compared to control animals, which could be blocked by melatonin. The inflammasome activation induced by morphine was mediated by the microglia. SiRNA knockdown or pharmacological inhibition of the NLRP3 abolished the morphine-induced inflammasome activation. Co-administration of melatonin and low-dose morphine had better analgesia effects in the murine models of pain and led to a lower NLRP3 inflammasome activity in brain tissues. Mice deficient for Nlrp3 had a higher nociceptive threshold and were less sensitive to develop morphine-induced analgesic tolerance and acetic acid-induced pain relative to wild-type animals. Concordantly, we observed a significantly elevated level of serum IL-1β, which indicates an increase of NLRP3 inflammasome activity associated with the reduced level of serum melatonin, in heroin-addicted patients relative to healthy individuals. Our results provide a solid basis for conducting a clinical trial with the co-administration of melatonin and morphine for the relief of severe pain.

Determination of Morphine, Fentanyl and Their Metabolites in Small Sample Volumes Using Liquid Chromatography Tandem Mass Spectrometry.

The USA and numerous other countries worldwide are currently experiencing a public health crisis due to the abuse of heroin and illicitly manufactured fentanyl. We have developed a liquid chromatography tandem mass spectrometry (LC-MS-MS)-based method for the detection of morphine, fentanyl and their metabolites, including morphine-3-glucuronide (M3G), morphine-6-glucuronide (M6G), normorphine, norfentanyl and deuterated internal standards in limited sample volumes with the limit of detection of 5.0/0.5ng/mL (morphine, M3G, M6G, normorphine/fentanyl, norfentanyl). The inter-assay precision (%CV) was less than 12% for all assays, and the inter-assay bias (%) was less than 5%. The ruggedness of the method, dilution effect and carryover were also investigated as part of the study. The simultaneous quantification of morphine, fentanyl and its metabolites via this simple and time- and cost-efficient method could be successfully applied to samples taken for pharmacokinetic evaluation (antemortem and postmortem) after a single dose of morphine or co-administration of morphine with other drugs (e.g., fentanyl) in rats.

Chronic morphine-mediated upregulation of high mobility group box 1 in the spinal cord contributes to analgesic tolerance and hyperalgesia in rats.

Analgesic tolerance and hyperalgesia hinder the long-term utility of opioids. We examined whether spinal high mobility group box 1 (HMGB1) is involved in morphine tolerance and its underlying mechanisms by using a model of repeated intrathecal (i.t.) injections of morphine. The results showed that chronic i.t. morphine exposure led to increased expression of HMGB1, Toll-like receptor 4 (TLR4), and receptor for advanced glycation end products (RAGE) and their mRNAs in the dorsal horn. Morphine challenge also promoted HMGB1 expression and release in cultured spinal neurons, but these effects were inhibited by TAK-242, naloxone (antagonists of TLR4), and TLR4 siRNA. Intrathecal coadministration of morphine with TAK-242 or PDTC (inhibitor of NF-κB activation) also reduced HMGB1 expression in the spinal cord. Repeated i.t. coinjections of morphine with glycyrrhizin (GL, an HMGB1 inhibitor) or HMGB1 siRNA prevented reduction of the maximal possible analgesic effect (MPAE) of morphine and alleviated morphine withdrawal-induced hyperalgesia. The established morphine tolerance and hyperalgesia were partially reversed when i.t. injections of GL or HMGB1 antibody started at day 7 of morphine injection. Repeated i.t. injections of morphine with HMGB1 siRNA inhibited the activation of NF-κB, but not that of JNK and p38. A single i.t. injection of HMGB1 in naïve rats caused pain-related hypersensitivity and reduction in MPAE. Moreover, phosphorylated NF-κB p65, TNF-α, and IL-1β levels in the dorsal horn were upregulated following this treatment, but this upregulation was prevented by coinjection with TAK-242. Together, these results suggest that morphine-mediated upregulation of spinal HMGB1 contributes to analgesic tolerance and hyperalgesia via activation of TLR4/NF-κB signaling, and the HMGB1 inhibitor might be a promising adjuvant to morphine in the treatment of intractable pain in the clinic.

The blockade of 5-HT1A receptors in the ventral tegmental area inhibited morphine/dextromethorphan-induced analgesia in pain rat models

The aim of the present study was to determine the involvement of the VTA 5-HT1A receptors in analgesia induced by the co-administration of morphine and dextromethorphan (DM). Male Wistar rats were bilaterally cannulated in the VTA by the stereotaxic instrument. The tail-flick and formalin tests were performed to assess nociception in the acute and tonic pain conditions respectively. The present data indicated that intraperitoneal (i.p.) administration of morphine increased the tail-flick latency (1–4 mg/kg) and decreased the pain score of formalin test (2–8 mg/kg), showing an analgesic effect. Co-administration of ineffective doses of morphine (1 or 2 mg/kg) with DM (30 mg/kg, i.p.) induced analgesia in both animal models. Interestingly, intra-VTA microinjection of 5HT1A receptors antagonist, S-WAY100-135 (0.5 and 1 µg/kg), inhibited the analgesic effect of morphine plus DM in both acute and tonic pain models. It should be considered that the same doses of DM or S-WAY100-135 by itself had no effects on antinociception in the animal models. Overall, these results indicated that systemic blockade of NMDA receptors via DM administration potentiated the response of a low dose of morphine to induce analgesic effect. Additionally, it seems that the VTA serotonergic system via 5HT1A receptors mediates the potentiative effect of DM on morphine-induced analgesia.

Determinants of high platelet reactivity in patients with acute coronary syndromes treated with ticagrelor

High platelet reactivity (HPR) is a risk factor for stent thrombosis, a potentially lethal complication of percutaneous coronary intervention. HPR is also associated with increased risk of myocardial infarction and death in invasively-treated patients with acute coronary syndrome (ACS). HPR occurs even in ACS patients treated with ticagrelor, a state-of-the-art antiplatelet agent, especially during the first hours of treatment. Patient-level pharmacodynamic data obtained from 102 ACS subjects enrolled in two prospective, pharmacodynamic trials were analysed in order to identify clinical features related with increased odds of on-ticagrelor HPR during the first two hours after ticagrelor loading dose in ACS patients. Presence of ST-segment elevation myocardial infarction (versus non-ST-segment elevation ACS) and morphine co-administration were the strongest predictors of HPR at 1 and 2 hours after ticagrelor loading dose according to linear regression analyses, multiple backward stepwise logistic regression analyses and generalized estimating equation model. By pinpointing simple to recognize clinical features, the results of this study facilitate identification of ACS patients who have the highest odds of HPR during the initial phase of treatment with ticagrelor, and who could potentially benefit from alternative treatment strategies.

Lack of Antinociceptive Cross-Tolerance With Co-Administration of Morphine and Fentanyl Into the Periaqueductal Gray of Male Sprague-Dawley Rats

Tolerance to the antinociceptive effect of mu-opioid receptor agonists, such as morphine and fentanyl, greatly limits their effectiveness for long-term use to treat pain. Clinical studies have shown that combination therapy and opioid rotation can be used to enhance opioid-induced antinociception once tolerance has developed. The mechanism and brain regions involved in these processes are unknown. The purpose of this study was to evaluate the contribution of the ventrolateral periaqueductal gray (vlPAG) to antinociceptive tolerance and cross-tolerance between administration and co-administration of morphine and fentanyl. Tolerance was induced by pretreating rats with morphine or fentanyl or low-dose combination of morphine and fentanyl into the vlPAG followed by an assessment of the cross-tolerance to the other opioid. In addition, tolerance to the combined treatment was assessed. Cross-tolerance did not develop between repeated vlPAG microinjections of morphine and fentanyl. Likewise, there was no evidence of cross-tolerance from morphine or fentanyl to the co-administration of morphine and fentanyl. Co-administration did not cause cross-tolerance to fentanyl. Cross-tolerance was only evident to morphine or morphine and fentanyl combined in rats pretreated with co-administration of low doses of morphine and fentanyl. This finding is consistent with the functionally selective signaling that has been reported for antinociception and tolerance after morphine and fentanyl binding to the mu-opioid receptor. This research supports the notion that combination therapy and opioid rotation may be useful clinical practices to decrease opioid tolerance and other side effects. PerspectiveThis preclinical study shows that there is a decrease in cross-tolerance between morphine and fentanyl within the periaqueductal gray, which is a key brain region in opioid antinociception and tolerance.

Effect of morphine use on oral P2Y12 platelet inhibitors in acute myocardial infarction: Meta-analysis

BackgroundMorphine is the recommended analgesic in acute myocardial infarction (AMI). This recommendation has come under scrutiny because of possible slow uptake of oral antiplatelet agents. ObjectiveWe performed a meta-analysis of all available studies in AMI patients treated with prasugrel or ticagrelor (P2Y12 inhibitors) that reported use of morphine prior to loading the antiplatelet agents to critically assess the safety of co-administration of morphine and the newer P2Y12 inhibitors. MethodsSeveral sources were searched from inception to December 2017 with inclusion of eight studies, largely observational. Mean difference (MD) was calculated for continuous variables, and standardized mean difference (SMD) for platelet function was assessed by the various platelet assays, 2 h after the loading dose of oral P2Y12 inhibitors. ResultsHigher platelet activity was noted among morphine group [SMD = 0.8, 95% confidence interval (CI) = 0.4–1.1, p < 0.01]. Morphine use caused higher odds of “high residual platelet reactivity” at 2 h (odds = 3.3, 95 %CI = 2.2–5.1, p < 0.01). Ticagrelor reached a lower plasma concentration in morphine group (MD = −481.8 ng/ml, 95% CI = −841.2 to −122.4 ng/ml, p < 0.01) with a higher vomiting rate (odds = 5.3, 95% CI = 2.5–11.1, p < 0.01). However, the composite of in-hospital mortality, stroke, and re-infarction was not significantly different between the groups (p = 0.83). ConclusionCo-administration of morphine with P2Y12 inhibitors possibly decreases their efficacy in platelet inhibition. However, this did not translate into higher adverse outcomes because of low event rates, inadequate for analysis. A large randomized study is needed to evaluate the narcotic-P2Y12 interaction.

The combination of opioid and neurotensin receptor agonists improves their analgesic/adverse effect ratio

Opioid and neurotensin (NT) receptors are expressed in both central and peripheral nervous systems where they modulate nociceptive responses. Nowadays, opioid analgesics like morphine remain the most prescribed drugs for the treatment of moderate to severe pain. However, despite their daily used, opioids can produce life-threatening side effects, such as constipation or respiratory depression. Besides, NT analogs exert strong opioid-independent analgesia. Here, we thus hypothesized that the combined use of opioid and NT agonists would require lower doses to produce significant analgesic effects, hence decreasing opioid-induced adverse effects. We used isobologram analyses to determine if the combination of a NT brain-penetrant analog, An2-NT(8-13) with morphine results in an inhibitory, synergistic or additive analgesic response. We found that intravenous administration of An2-NT(8-13) reduced by 90% the nocifensive behaviors induced by formalin injection, at the dose of 0.018 mg/kg. Likewise, subcutaneous morphine reduced pain by 90% at 1.8 mg/kg. Importantly, isobologram analyses revealed that the co-injection of An2-NT(8-13) with morphine induced an additive analgesic response. We finally assessed the effects of morphine and An2-NT(8-13) on the gastrointestinal tract motility using the charcoal meal test. As opposed to morphine which significantly reduced the intestinal motility at the analgesic effective dose of 1.8 mg/kg, An2-NT(8-13) did not affect the charcoal meal intestinal transit at 0.018 mg/kg. Interestingly, at the dose providing 90% pain relief, the co-administration of morphine with An2-NT(8-13) had a reduced effect on constipation. Altogether, these results suggest that combining NT agonists with morphine may improve its analgesic/adverse effect ratio.

The analgesic interaction of tramadol and morphine in rats: An isobolographic study.

In order to assess possible synergistic antinociceptive interactions, the analgesic effects of intra-peritoneal tramadol and morphine administered either separately or in combination were determined using tail-flick latency test following exposure to radiant heat in rats. Groups of eight male Sprague-Dawley rats received either tramadol (3.90, 7.00, 12.50, and 22.20 mg kg-1) and morphine (1.26, 2.25, 4.00 and 7.10 mg kg-1) or a combination of tramadol and morphine (4 different combinations). The baseline latency was obtained before drug injection for each rat, then at 15, 30, 45, 60 and 75 min after injection. The effective dose (ED)50 for either tramadol or morphine individually was 11.70 mgkg-1 and 2.26 mg kg-1, respectively. Based on isobolographic analysis, the ED50 values obtained by drug combination were significantly less than the calculated additive values; which indicates that the co-administration of tramadol and morphine produces synergistic antinociception in the radiant heat tail-flick assay. Combination of morphine and tramadol administered intra-peritoneally can be used for the control of acute pain in rats.

The dorsal hippocampal group III metabotropic glutamate receptors are involved in morphine effect on memory formation in male mice

This study investigated the role of dorsal hippocampal (CA1) group III metabotropic glutamate (mGlu) receptors in impairment of memory formation and state-dependent memory induced by morphine. For this purpose, the CA1 area was cannulated and one-trial passive avoidance task was selected to assess the memory function. Morphine was administrated subcutaneously (s.c.) and mGlu receptors agonist or antagonist were microinjected into CA1 regions. The obtained results indicated that pre-training administration of morphine (5 mg/kg; s.c.) decreased memory retention. Moreover, pre-test administration of morphine (5 mg/kg; s.c.) induced morphine state–dependent memory retention under pre-training morphine effect (5 mg/kg; s.c.). Although, intra-CA1 microinjection of lower doses of group III mGlu receptors agonist, L-AP4, (10 and 20 mmol/mouse) and antagonist, CPPG, (10 and 15 mmol/mouse) did not affect memory retention, but higher dose of the drugs (30 mmol/mouse) decreased memory retention. Pre-test microinjection of L-AP4 (10, 20 and 30 mmol/mouse; intra-CA1) had no effect on morphine-induced amnesia, but same doses of L-AP4 plus an effective dose of morphine (1 mg/kg; s.c.) reversed morphine-induced amnesia. Interestingly, amnesia induced by pre-training morphine (5 mg/kg; s.c.) was significantly reversed by pre-test administration of CPPG (30 mmol/mouse; intra-CA1). On the other hand, pre-test co-administration of CPPG (10 and 15 mmol/mouse; intra-CA1) and morphine (5 mg/kg; s.c.) following pre-training morphine (5 mg/kg; s.c.) decreased memory retention. Taken together, our results suggested that morphine effects on memory formation might be mediated via the activity of dorsal hippocampal metabotropic glutamate receptors.

Should STEMI Patients Receive Opiate Analgesia? The Morphine Paradox.

The very significant benefit of P2Y12 receptor inhibitor administration in patients with ST-elevation myocardial infarction (STEMI), in reducing future ischaemic events and stent thrombosis, is undisputed. Morphine analgesia is very frequently co-administered to these patients for pain relief, along with antiplatelet therapy, at the time of presentation, and prior to reperfusion with primary percutaneous coronary intervention. Research and online content related to opiates use in STEMI was reviewed. Bibliographies of retrieved studies were searched manually for additional studies and reviews. There is sufficient data from pharmacokinetic and pharmacodynamic studies showing that the co-administration of morphine with oral P2Y12 receptor inhibitor results in delayed antiplatelet effects. However, whether this results in adverse outcomes remains unclear. Data from studies reporting the effect of morphine on clinical outcomes in STEMI are inconsistent, although they tend to be underpowered to show an effect on hard clinical outcomes, but some clearly show a relationship between morphine use and infarct size. Strategies to overcome the potentially significant negative impact of morphine on platelet reactivity in STEMI are discussed. Whilst clearly definitive, adequately powered, randomised controlled trials are lacking, we would recommend avoiding the combination of morphine with oral P2Y12 receptor inhibitors and recommend alternative strategies including intravenous platelet inhibitor strategies, in high risk patients.

NMDA receptor antagonists attenuate intrathecal morphine-induced pruritus through ERK phosphorylation

Pruritus is the most common complication of intrathecal morphine; however, its exact molecular mechanism is unclear, and treatment is challenging. The analgesic effect of N-methyl-D-aspartate (NMDA) receptor antagonists and the morphine-associated increase in NMDA receptor activation suggest potential role of NMDA receptor in the spinal itch sensation. Male C57BL/6 mice were given intrathecal morphine to induce scratching behavior. The effects of NMDA, ketamine, ifenprodil and U0126 on morphine-induced pruritus and analgesia were evaluated also. The number of scratching responses was counted for 30 min post-injection to evaluate pruritus. A warm-water tail immersion assay was conducted before and until 120 min post-injection at 30-min intervals. Percent of maximal possible effect (%MPE) and area under curve (AUC) were calculated based on tail-flick latency to evaluate analgesic efficacy. Compared with control treatment, intrathecal morphine elicited an obvious scratching response and analgesic effect in a dose dependent manner. Ketamine (1 μg), ifenprodil (0.1 μg) and U0126 (0.1 μg and 1.0 μg) all significantly attenuated morphine induced scratches. Ifenprodil (0.1 μg) injection significantly prolonged the analgesic effect of intrathecal morphine. The ERK1/2 phosphorylation induced by intrathecal morphine was inhibited by ketamine, ifenprodil and U0126 as well. U0126 inhibited morphine-induced pruritus with no effect on its analgesia. Therefore, intrathecal coadministration of morphine with NMDA receptor antagonists ketamine and ifenprodil alleviated morphine-induced scratching. Intrathecal morphine increased ERK phosphorylation in the lumbar spinal dorsal horn, which may be related with morphine-induced pruritus, and was counteracted by NMDA receptor antagonists.

Effects of Cannabinoid Type 2 Receptor Agonist AM1241 on Morphine-Induced Antinociception, Acute and Chronic Tolerance, and Dependence in Mice

Morphine is a potent opioid analgesic used to alleviate moderate or severe pain, but the development of drug tolerance and dependence limits its use in pain management. Previous studies showed that cannabinoid type 2 (CB2) receptor ligands may modulate opioid effects. However, there is no report of the effect of CB2 receptor agonist on acute morphine tolerance and physical dependence. We therefore investigated the effect of a CB2 receptor agonist (AM1241) on morphine-induced morphine tolerance and physical dependence in mice. Repeated coadministration of AM1241 (1 or 3mg/kg intraperitoneally) and morphine (10mg/kg subcutaneously) for 7days increased the mechanical paw withdrawal threshold in mice as measured by the von Frey filament test, and 3mg/kg AM1241 in combination with morphine increased the thermal paw withdrawal latency as measured by the hot-plate test. Combination with 3mg/kg AM1241 and morphine increased acute morphine antinociception. Coadministration of 1 or 3mg/kg AM1241 and morphine reduced acute morphine tolerance, and 3mg/kg AM1241 reduced chronic morphine tolerance. Coadministration of 1 or 3mg/kg AM1241 and morphine reduced naloxone-precipitated withdrawal jumping, but not diarrhea. Coadministration of AM1241 and morphine did not inhibit spontaneous locomotor activity. Pretreatment with 3mg/kg AM1241 decreased the chronic morphine-induced Iba1 expression in spinal cord. Coadministration of AM1241 (3 mg/kg) reduced the production of interleukin-1β, tumor necrosis factor-α, and interleukin-6 induced by long-term and acute morphine treatment. Our findings suggest that the coadministration of the CB2 receptor agonist and morphine could increase morphine antinociception and reduce morphine tolerance and physical dependence in mice.Perspective:The combination of a CB2 agonist and morphine may provide a new strategy for better treatment of acute and chronic pain and prevention of opioid tolerance and dependence. This finding may also provide a clue for the treatment of opioid tolerance and dependence in clinics.

Morphine Interaction with Aspirin: a Double-Blind, Crossover Trial in Healthy Volunteers

Aspirin is a cornerstone in the antiplatelet therapy for acute coronary syndromes. Coadministration of morphine may potentially influence the intestinal absorption, pharmacokinetics, and pharmacodynamics, as seen with P2Y12 inhibitors. In this trial, healthy volunteers were randomized to receive morphine (5 mg, i.v. bolus injection) at one of seven different time points before, after, or with aspirin (162 mg, p.o.) in a double-blind, placebo-controlled fashion. After a 14-day washout, subjects received placebo instead of morphine. Pharmacokinetics were determined by liquid chromatography, and aspirin's effects were measured by platelet function tests (whole-blood platelet aggregation: multiplate, platelet plug formation: PFA-100). Morphine increased the total acetylsalicylic acid exposure by 20% compared with placebo when given simultaneously with aspirin, whereas Cmax and tmax were not altered. Morphine had no significant effect on aspirin-induced platelet inhibition. In contrast to coadministration with P2Y12 inhibitors, morphine appears to have negligible interaction with aspirin.

(249) - Role of nerve growth factor/tyrosine kinase receptor a signaling in the plasma of morphine tolerant rat

Morphine is extensively used as an analgesic in pain management. However, repeated administration of morphine produces tolerance. In the central nervous system, nerve growth factor (NGF) and its receptor, tyrosine kinase receptor A (TrkA), are involved in pain, analgesia, and tolerance mechanisms. Additionally, multiple clinical and animal studies have shown changes in circulating NGF in various neurological disorders. In the present study, we investigated the effects of chronic morphine treatment on the NGF-TrkA pathway in morphine-induced tolerant rats. Animals were treated with morphine with or without concomitant administration of the tyrosine kinase receptor A antagonist K252a. The morphine (10 mg/kg; subcutaneous) or K252a (80 µg/kg; intraperitoneal) treatment regime was 2x/day for five days. On the sixth day, a single injection of morphine/K252a was administered. The development of tolerance was assessed by changes in paw withdrawal latency (PWL) to noxious thermal stimuli (Thermal test). The change in plasma NGF levels was measured by ELISA. PWL progressively decreased in rats that received repeated morphine treatments indicating development of antinociceptive and morphine tolerance. Morphine tolerant rats showed two fold increases in the plasma NGF level compared to saline-treated control rats. Co-administration of morphine and K252a increased PWL and also reduced the plasma NGF levels. These initial findings suggest that plasma NGF-TrkA signaling contributes to the development of opioid tolerance. This research was supported by Congressionally Directed Medical Research Programs- Applied Pain Research grant (MR157005C).

Safety and effectiveness of coadministration of intrathecal sufentanil and morphine in hyperbaric bupivacaine-based spinal anesthesia for cesarean section

Subarachnoid block is a widely used technique for cesarean section. Opioids adding to the local anesthetics can improve its quality. In this prospective, randomized, double blind, controlled trial, we compared the effects of coadministration of intrathecal sufentanil and morphine with intrathecal sufentanil and a single administration of subcutaneous morphine. Sixty-four pregnant women scheduled for elective cesarean section under spinal anesthesia were assigned to two groups according to the way of administration of morphine: intrathecal sufentanil (5 microg) plus intrathecal morphine (150 microg) (ITM group), and intrathecal sufentanil (5 microg) plus single administration of 10 mg subcutaneous morphine (SCM group). In both groups, the local anesthetic used was hyperbaric bupivacaine 0.5 percent (10 mg). Both groups received 1 g acetaminophen every 6 hours. In the postoperative period, pain was recorded on a 0-100 visual analog scale (VAS) and intravenous tramadol (100 mg) was administered if VAS score was >40 mm. Collateral effects, such as nausea, itching, respiratory depression, and sedation were assessed. VAS scores at rest and on coughing were significantly higher in the SCM group than in the ITM group between 3 and 24 hours. The mean titrated dose of tramadol consumed was also significantly greater in the SCM group than in the ITM group (p < 0.05). The time to first administration of tramadol was lower in the SCM group versus the ITM group (p < 0.05). The incidence of nausea was significantly lower in the SCM group than in the ITM group (p < 0.05). There was no significant group difference in the incidence of pruritus (p > 0.05). In conclusion, coadministration of sufentanil and morphine into the subarachnoid space was effective and provided longer pain relief than intrathecal sufentanil plus a single injection of subcutaneous morphine, despite a higher incidence of side effects such as nausea and vomiting.